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Monte Carlo‐minimized energy profile of estradiol in the ligand‐binding tunnel of 17β‐hydroxysteroid dehydrogenase: Atomic mechanisms of steroid recognition
Author(s) -
Zhorov Boris S.,
Lin ShengXiang
Publication year - 2000
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(20000301)38:4<414::aid-prot7>3.0.co;2-x
Subject(s) - steroid , dehydrogenase , monte carlo method , hydroxysteroid dehydrogenase , chemistry , endocrinology , enzyme , medicine , biochemistry , hormone , mathematics , statistics
17β‐Estradiol (E 2 ) is a potent stimulator of certain forms of breast cancer. The final step of E 2 biosynthesis is catalyzed by the estrogenic 17β‐hydroxysteroid dehydrogenase (17β‐HSD1), which is an important target for anticancer drugs. X‐ray crystallography indicated that the binding site for the steroids has a tunnel‐like shape. We have used a Monte Carlo–Minimization (MCM) protocol to explore possibilities of interactions of E 2 with the binding site tunnel of 17β‐HSD1. The enzyme was represented by flexible residues having at least one atom within 6 Å from either E 2 or NADP (as seen in a crystal ternary complex) and by rigid residues having at least one atom within 10 Å from E 2 or NADP. Special constraints were used to pull the substrate 10 Å along the tunnel with 1 Å step; the complex was MCM‐optimized at each position of the steroid. The optimal binding mode of E 2 in 17β‐HSD agrees with the crystallographic data; however, wide and flat minima of the MCM profile suggest alternative modes of the steroid binding. The advance of the steroid along the tunnel is accompanied by essential conformational rearrangements of the enzyme side chains, noticeable rotation of the substrate along its longitudinal axis, and certain conformational deformations of the substrate. The contributions of the enzyme residues and of the steroid atoms to the intermolecular energy were estimated. Proteins 2000;38:414–427. © 2000 Wiley‐Liss, Inc.